Practice Essentials

Metastasis to the brain is the most feared complication of systemic cancer and the most common intracranial tumor in adults. The incidence of brain metastasis is rising with the increase in survival of cancer patients. Currently, cancer patients live longer as a result of important advances in cancer diagnosis and management—particularly, the widespread use of MRI to detect small metastases. Approximately 40% of intracranial neoplasms are metastatic. Multiple, large autopsy series suggest that, in order of decreasing frequency, lung (40%), breast (20%), melanoma (10%), and enteric cancers (6%) are the most common primary tumors to metastasize to the brain.
[1] (See the image below.)

Sagittal T1-weighted precontrast and postcontrast MRI. A surgically proven, solitary right parietal metastasis is seen with a single, 1-cm, enhancing right parietal nodule and extensive surrounding edema typical of a metastasis.

Brain metastases are an increasingly important cause of morbidity and mortality in cancer patients. Thus, brain metastasis presents a therapeutic challenge for the treating physician and is an emotionally and physically debilitating event for the patient. Early diagnosis and aggressive treatment of brain metastasis may result in remission of brain symptoms and may enhance the quality of the patient's life and prolong survival.

The prognosis for patients with brain metastases typically is poor. Most available treatment is palliative; however, consideration should be given to prolonging the patient's quality of life through specific therapy to the brain. Of particular relevance to imaging is the fact that for patients with a solitary brain metastasis who undergo treatment by surgical resection, the survival rate after 1 year is approximately doubled. Furthermore, evidence suggests that minimally invasive stereotactic radiosurgery can be safely used for patients with up to 10 brain metastasis nodules.
[2] The radiologist plays a primary role in the management of cancer patients by providing accurate determination of the number, size, and location of metastatic lesions, which is crucial for selecting the most appropriate treatment method.
[3]

Preferred examination

Most patients with a known primary tumor undergo imaging studies when neurologic signs and symptoms develop. Magnetic resonance imaging (MRI) with contrast enhancement currently is the procedure of choice, because MRI is more sensitive and specific than other imaging modalities in determining the presence, location, and number of metastases.
[1] However, contrast-enhanced computed tomography (CT) scanning is used widely because of its accessibility and low cost.
[4, 5, 6, 7, 8] In situations where MR imaging is not possible, contrast-enhanced CT can be helpful in detecting areas of neurovascular unit disruption and defining the contrast-enhancing tumor burden for large areas of disease.

Even though it is less sensitive than MR imaging in tumor detection and characterization, non-contrast CT imaging is commonly performed as the first screening modality in emergent situations where a patient presents with new-onset neurologic symptoms, because it is very sensitive in detecting the acute life-threatening complications (ie, hemorrhage, hydrocephalus, and herniation) of metastatic disease.
[1]

With regard to screening for intracranial metastases, no consensus has been reached concerning when to use CT or MRI for initial staging evaluation of a patient with cancer. However, brain MRI for patients with primary cancers that frequently metastasize to the brain (eg, bronchogenic carcinoma) is probably cost-effective. Numerous studies have shown that contrast-enhanced MRI detects 2-3 times as many lesions as contrast-enhanced CT, especially lesions that are less than 5 mm in diameter. In addition, approximately 20% of patients with solitary metastatic lesions on CT show multiple lesions on MRI. The decision to perform imaging for patients with other cancers is made on the basis of the clinical evaluation.

In the presence of multiple cerebral metastases from an unknown primary source, a limited search for the primary tumor is of value; such a search includes a chest radiograph, breast examination and mammography, and abdominal ultrasound (US). An extensive search for an occult malignancy is unrewarding. Surgery may be required for patients presenting with a solitary intracranial tumor or to search for a possible primary tumor.

Approximately one third of patients operated on for a single cerebral metastasis diagnosed with contrast-enhanced CT probably have more than one lesion. Contrast-enhanced MRI is more sensitive than CT in detecting the number of cerebral metastases.

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Radiography

Skull radiographs may detect multiple lytic or sclerotic deposits when the metastatic process involves the cranium. Lung and breast tumors are the most common primary malignancies to affect the skull. Multiple lytic lesions secondary to multiple myeloma tend to be uniformly small. Blastic metastases are seen in patients with primary prostate cancer or in patients who have undergone treatment for breast cancer. Calcifications are uncommon in metastases but do occur in primary adenocarcinoma, osteogenic sarcoma, and lung and breast carcinoma. Plain radiographs are not helpful in detecting metastatic disease of the brain.

Multiple lytic or blastic lesions are highly suggestive of a metastatic process. Solitary lesions must be differentiated from other pathologic processes affecting the skull vault.

Normal anatomic variants, such as emissary vein, arachnoid granulation, and bone island, may mimic a metastatic lesion in a known cancer patient. Use of CT with bone windows may eliminate false diagnoses.

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Computed Tomography

Metastases frequently are multiple; they are seen at the junction of gray and white matter, usually with significant surrounding edema.
[9, 10]

(See the images below.)

Contrast-enhanced CT demonstrates multiple enhancing metastatic nodules at the gray-white junction in a patient with known colon cancer.

On noncontrast CT, the density of metastatic lesions may be less than, equal to, or greater than that of adjacent brain parenchyma. Most of the patterns are variable and are nondiagnostic, as shown in the images below.

Precontrast- and postcontrast-enhanced CT demonstrates multiple ring-enhancing lesions (thick, peripheral, ringlike) in the left hemisphere with prominent surrounding edema and mass effect in a patient with known lung cancer.

IV administration of contrast material (30-40 g iodine) increases the diagnostic accuracy of CT. Most metastases enhance after a standard dose of IV contrast. Use of a higher dose of contrast (80-85 g of iodine) and delaying scanning by 1-3 hours after injection of the contrast agent lead to a further increase in the detection of multiple metastases; such an approach is appropriate if MRI is not available.

The detection of additional metastases has important diagnostic and therapeutic implications. In cases in which there is no known primary cancer, if a solitary lesion is found on routine enhanced CT, the presence of an additional lesion may suggest a metastatic process, provided the solitary lesion is believed to be a primary lesion. In cases involving a solitary metastatic lesion of the brain, detection of an additional lesion may have a bearing on treatment; with multiple lesions, surgical treatment may be forgone in favor of chemotherapy, radiation therapy, or both.

Contrast-enhanced CT is effective in detecting major leptomeningeal spread. Contrast-enhancing subdural or epidural metastases may be seen, usually secondary to calvarial lesions. Of breast, lung, prostate, and renal-cell neoplasms, 5% metastasize to the calvarium; of these, 15% extend into the subdural space. See the images below for contrast-enhanced CTs.

Precontrast- and postcontrast-enhanced CT of a patient with breast cancer. Linear enhancement in the anterior falx and medial sulci of both frontal lobes suggests leptomeningeal and dural carcinomatosis.

Degree of confidence

On findings of multiple, enhancing solid lesions at the gray matter–white matter junction and prominent surrounding edema in a patient with known primary cancer, a diagnosis of metastases may be confidently made. Approximately 90% of patients with a history of cancer who present with a single supratentorial lesion have brain metastases.

Patients with multiple lesions are even more likely to have metastatic disease. Before undergoing definitive therapy, patients who are found to have a single metastasis on contrast-enhanced CT should undergo a contrast-enhanced MRI examination, if facilities for such an examination are available.

Routine cranial CT is useful in the staging of cancer in the patient with non–small-cell lung cancer; cranial CT has a sensitivity of 92%, a specificity of 99%, and an accuracy of 98% in detecting brain metastases. Contrast-enhanced CT is perhaps the best method to identify calvarial metastases. In studies comparing contrast-enhanced CT with contrast-enhanced MRI, approximately 20% of patients who demonstrated a single lesion on CT demonstrated multiple lesions on MRI. Mostly, the lesions missed on contrast-enhanced CT were smaller (<2 cm in diameter) and were located next to the bone in a frontotemporal location. Dural-based metastases may mimic meningioma.

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Magnetic Resonance Imaging

Coronal contrast-enhanced T1-weighted MRI. Multiple solid and cystic supratentorial and infratentorial mass lesions are seen in a patient with known breast cancer. Note the cystic, ring-enhancing, and solid patterns.

Lesions are isointense to mildly hypointense on T1-weighted images; they are hyperintense on T2-weighted images or with fluid attenuation inversion recovery.

Surrounding edema is relatively hypointense on fluid attenuation inversion recovery and on T1-weighted images; they are hyperintense on T2-weighted images.

Hemorrhagic metastases or melanoma lesions are hyperintense on T1-weighted images.

On T2-weighted images, mucinous adenocarcinoma may be hypointense because of calcification; hemorrhagic metastases may be hypointense because of the chronic breakdown of blood products.

Following administration of a contrast agent, solid, nodular (see first image below), or irregular ring patterns of enhancement are seen. Nonenhancing lesions (see second image below) are less likely to be metastases.

Axial contrast-enhanced T1-weighted MRI of a patient with known lung cancer. Multiple, small ring-enhancing lesions are seen in both hemispheres.

T2-weighted and postcontrast T1-weighted MRI of a patient with uterine cancer. Well-defined, nonenhancing, round lesion with fluid signal intensity is seen in the right temporal lobe, with prominent surrounding edema. This is a surgically proven cystic metastasis.

Contrast-enhanced MRI is the best method for detection of meningeal tumor seeding, which appears as abnormal dural enhancement. This is a nonspecific finding; however, in the correct clinical setting, it correlates with the presence of sheets of tumor cells affecting the meninges.

Approximately 30% of patients with metastatic disease to the CNS will present with a solitary brain parenchymal lesion, and differentiating a solitary metastasis from high-grade glioma is clinically important, as medical staging, surgical planning, and therapeutic decisions are drastically different. It is difficult to distinguish primary glioma from an intercranial metastasis based on standard magnetic resonance imaging (MRI). There are reports of successful use of diffusion-weighted and perfusion-weighted imaging and proton-MR spectroscopy for differentiation of brain gliomas from solitary brain metastases.
[1, 17]

High-resolution stereotactic MRI at the time of gamma knife surgery may detect additional brain metastases, decreasing the incidence of, and lengthening the time to, distant recurrences.
[18]

Gadolinium-based contrast agents have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD).
[19] NSF/NFD has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness.

Degree of confidence

Gadolinium-enhanced MRI is superior to contrast-enhanced CT in the diagnosis of brain metastases. Gadolinium-enhanced MRI has the following advantages:

Provides less partial-volume effects, particularly for lesions adjacent to bones

Provides direct multiplanar imaging

Use of magnetization transfer with single-dose gadolinium administration is roughly equivalent to triple-dose, postcontrast, spin-echo imaging in detecting lesions and lesion conspicuity.

It has been shown that treatment with dexamethasone leads to a reduction in evidence on MRI of peritumoral edema and, occasionally, a lessening in the extent of contrast enhancement. If a lesion is found and a definitive diagnosis cannot be established, biopsy should be performed.

High-dose gadoteridol (ProHance) is better able to detect additional smaller lesions than routine-dose gadopentetate dimeglumine (Magnevist). Detection of additional lesions is important when considering surgical treatment of a solitary lesion. Magnetization transfer used with routine-dose gadolinium contrast is closely comparable to the high-dose technique.

False positives/negatives

On imaging, dural-based metastases (see first image below) may resemble meningioma. Leptomeningeal carcinomatosis (see second image below) may resemble chronic meningitis; however, an appropriate history or detection of primary cancer may be sufficient for establishing the diagnosis. Leptomeningeal enhancement may occur after the administration of radiation or following extra-axial hemorrhage; it may also occur below a craniotomy site. Single or multiple ring-enhancing lesions with edema may resemble infectious processes. Solitary lesions resemble primary brain tumors.

Sagittal contrast-enhanced MRI of a patient with known prostate cancer. The solitary enhancing right parietal extra-axial lesion is a surgically proven dural metastasis.

Coronal contrast-enhanced MRI of a patient with known melanoma. Note the linear enhancement in the sulci and brain surface of the right frontal and temporal lobes suggestive of leptomeningeal carcinomatosis. The cancer was proven by cerebrospinal fluid cytology.

Radionuclide studies are sensitive but are highly nonspecific. In studies involving a small number of patients, FDG-PET demonstrated low sensitivity and low specificity. Currently, FDG-PET is not considered superior to CT or MRI in the initial evaluation of suspected brain metastases.

In older reports, radionuclide imaging was reported to detect intracerebral metastases in approximately 90% of patients, but the findings were nonspecific. Neoplasm, inflammation, vascularity, or trauma may cause the abnormal uptake. FDG-PET has been reported to detect approximately two thirds of brain metastases resulting from systemic cancer.
[25, 26]

Lizarraga et al reported that 18F-DOPA positron emission tomography (PET) is able to distinguish recurrent or progressive brain metastases from late or delayed radiation injury. 18F-DOPA PET has been shown to have a sensitivity and a specificity of 81% and 84%, respectively, in the detection of relapse of secondary brain tumor after treatment, as compared to FDG-PET (65% and 80%, respectively).
[27]

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Angiography

Angiography currently is not used as a primary diagnostic procedure for metastatic disease. Rarely, preoperative angiography and embolization of large hypervascular metastases from renal and thyroid cancer may be useful.

Angiography is useful in evaluating tumor vascularity in selected mesastatic lesions before biopsy is performed. The results of angiography are nonspecific in the diagnosis of metastases.

Sagittal T1-weighted precontrast and postcontrast MRI. A surgically proven, solitary right parietal metastasis is seen with a single, 1-cm, enhancing right parietal nodule and extensive surrounding edema typical of a metastasis.

Contrast-enhanced CT demonstrates multiple enhancing metastatic nodules at the gray-white junction in a patient with known colon cancer.

Precontrast- and postcontrast-enhanced CT demonstrates multiple ring-enhancing lesions (thick, peripheral, ringlike) in the left hemisphere with prominent surrounding edema and mass effect in a patient with known lung cancer.

Coronal contrast-enhanced T1-weighted MRI. Multiple solid and cystic supratentorial and infratentorial mass lesions are seen in a patient with known breast cancer. Note the cystic, ring-enhancing, and solid patterns.

Axial contrast-enhanced T1-weighted MRI of a patient with known lung cancer. Multiple, small ring-enhancing lesions are seen in both hemispheres.

Sagittal contrast-enhanced MRI of a patient with known prostate cancer. The solitary enhancing right parietal extra-axial lesion is a surgically proven dural metastasis.

Coronal contrast-enhanced MRI of a patient with known melanoma. Note the linear enhancement in the sulci and brain surface of the right frontal and temporal lobes suggestive of leptomeningeal carcinomatosis. The cancer was proven by cerebrospinal fluid cytology.

Precontrast- and postcontrast-enhanced CT of a patient with breast cancer. Linear enhancement in the anterior falx and medial sulci of both frontal lobes suggests leptomeningeal and dural carcinomatosis.

Noncontrast CT of a patient with lung cancer. Multiple high-density lesions are seen in both cerebral hemispheres, suggestive of hemorrhagic metastases.

Contrast-enhanced CT and bone CT of a patient with breast cancer. Multiple irregular and aggressive lytic lesions are seen in the calvarium with dural-based metastases.

Precontrast- and postcontrast-enhanced CT scan of a patient with mucin-secreting adenocarcinoma of the stomach. Multiple calcified nodules are seen in the surgically proven metastasis.

T2-weighted and postcontrast T1-weighted MRI of a patient with uterine cancer. Well-defined, nonenhancing, round lesion with fluid signal intensity is seen in the right temporal lobe, with prominent surrounding edema. This is a surgically proven cystic metastasis.

James G Smirniotopoulos, MD Chief Editor, MedPix®, Lister Hill National Center for Biomedical Communications, US National Library of Medicine; Professorial Lecturer, Department of Radiology, George Washington University School of Medicine and Health Sciences